tbuckley/cabot-search huggingface dataset:
Safe and effective off-the-shelf immunotherapy based on CAR.CD123-NK cells for the treatment of acute myeloid leukaemia
Authors: Simona Caruso, Biagio De Angelis, Francesca Del Bufalo, Roselia Ciccone, Samantha Donsante, Gabriele Volpe, Simona Manni, Marika Guercio, Michele Pezzella, Laura Iaffaldano, Domenico Alessandro Silvestris, Matilde Sinibaldi, Stefano Di Cecca, Angela Pitisci, Enrico Velardi, Pietro Merli, Mattia Algeri, Mariachiara Lodi, Valeria Paganelli, Marta Serafini, Mara Riminucci, Franco Locatelli, Concetta Quintarelli
Journal: Journal of Hematology & Oncology (2022)

Abstract Background Paediatric acute myeloid leukaemia (AML) is characterized by poor outcomes in patients with relapsed/refractory disease, despite the improvements in intensive standard therapy. The leukaemic cells of paediatric AML patients show high expression of the CD123 antigen, and this finding provides the biological basis to target CD123 with the chimeric antigen receptor (CAR). However, CAR.CD123 therapy in AML is hampered by on-target off-tumour toxicity and a long “vein-to-vein” time. Methods We developed an off-the-shelf product based on allogeneic natural killer (NK) cells derived from the peripheral blood of healthy donors and engineered them to express a second-generation CAR targeting CD123 (CAR.CD123). Results CAR.CD123-NK cells showed significant anti-leukaemia activity not only in vitro against CD123 + AML cell lines and CD123 + primary blasts but also in two animal models of human AML-bearing immune-deficient mice. Data on anti-leukaemia activity were also corroborated by the quantification of inflammatory cytokines, namely granzyme B (Granz B), interferon gamma (IFN-γ) and tumour necrosis factor alpha (TNF-α), both in vitro and in the plasma of mice treated with CAR.CD123-NK cells. To evaluate and compare the on-target off-tumour effects of CAR.CD123-T and NK cells, we engrafted human haematopoietic cells (hHCs) in an immune-deficient mouse model. All mice infused with CAR.CD123-T cells died by Day 5, developing toxicity against primary human bone marrow (BM) cells with a decreased number of total hCD45 + cells and, in particular, of hCD34 + CD38 − stem cells. In contrast, treatment with CAR.CD123-NK cells was not associated with toxicity, and all mice were alive at the end of the experiments. Finally, in a mouse model engrafted with human endothelial tissues, we demonstrated that CAR.CD123-NK cells were characterized by negligible endothelial toxicity when compared to CAR.CD123-T cells. Conclusions Our data indicate the feasibility of an innovative off-the-shelf therapeutic strategy based on CAR.CD123-NK cells, characterized by remarkable efficacy and an improved safety profile compared to CAR.CD123-T cells. These findings open a novel intriguing scenario not only for the treatment of refractory/resistant AML patients but also to further investigate the use of CAR-NK cells in other cancers characterized by highly difficult targeting with the most conventional T effector cells.
GATA-3 is a proto-oncogene in T-cell lymphoproliferative neoplasms
Authors: Xiangrong Geng, Chenguang Wang, Xin Gao, Pinki Chowdhury, Jonathan Weiss, José A. Villegas, Badeia Saed, Thilini Perera, Ying Hu, John Reneau, Maria Sverdlov, Ashley Wolfe, Noah Brown, Paul Harms, Nathanael G. Bailey, Kedar Inamdar, Alexandra C. Hristov, Trilokraj Tejasvi, Jaime Montes, Carlos Barrionuevo, Luis Taxa, Sandro Casavilca, J. Luís Alberto de Pádua Covas Lage, Hebert Fabrício Culler, Juliana Pereira, John S. Runge, Tingting Qin, Lam C. Tsoi, Hanna S. Hong, Li Zhang, Costas A. Lyssiotis, Rintaro Ohe, Tomomi Toubai, Alejandro Zevallos-Morales, Carlos Murga-Zamalloa, Ryan A. Wilcox
Journal: Blood Cancer Journal (2022)

Neoplasms originating from thymic T-cell progenitors and post-thymic mature T-cell subsets account for a minority of lymphoproliferative neoplasms. These T-cell derived neoplasms, while molecularly and genetically heterogeneous, exploit transcription factors and signaling pathways that are critically important in normal T-cell biology, including those implicated in antigen-, costimulatory-, and cytokine-receptor signaling. The transcription factor GATA-3 regulates the growth and proliferation of both immature and mature T cells and has recently been implicated in T-cell neoplasms, including the most common mature T-cell lymphoma observed in much of the Western world. Here we show that GATA-3 is a proto-oncogene across the spectrum of T-cell neoplasms, including those derived from T-cell progenitors and their mature progeny, and further define the transcriptional programs that are GATA-3 dependent, which include therapeutically targetable gene products. The discovery that p300-dependent acetylation regulates GATA-3 mediated transcription by attenuating DNA binding has novel therapeutic implications. As most patients afflicted with GATA-3 driven T-cell neoplasms will succumb to their disease within a few years of diagnosis, these findings suggest opportunities to improve outcomes for these patients.
Bivalirudin plus a high-dose infusion versus heparin monotherapy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a randomised trial
Authors: Yi Li, Zhenyang Liang, Lei Qin, Mian Wang, Xianzhao Wang, Huanyi Zhang, Yin Liu, Yan Li, Zhisheng Jia, Limin Liu, Hongyan Zhang, Jun Luo, Songwu Dong, Jincheng Guo, Hengqing Zhu, Shengli Li, Haijun Zheng, Lijun Liu, Yanqing Wu, Yiming Zhong, Miaohan Qiu, Yaling Han, Gregg W Stone
Journal: The Lancet (2022)
We wish you a smooth takeoff! Launching “Intensive Care Fundamentals”: an ESICM educational initiative for newcomers to intensive care unit
Authors: Frantisek Duska, Maurizio Cecconi, Frantisek Duska, Mauricio Cecconi, Mo Al-Haddad, Frauke Weidanz, Anne Le Roy, Raj Saha, Anne Mecklenburg, Eumorfia Kondil, Nathan Nielsen, María Martinéz Martinéz, Rahul Costa-Pinto, Joanna Berger, Jerome Cockings, Carole Boulanger, Gabriel Garcia Rosenbaum, Alexander Christian Waschwill, Joel Alexandre, Melania Istrate, Estelle Pasquier, Elisa Vera, Anita Barth, Margeaux Osselaer
Journal: Intensive Care Medicine (2022)
MACHETE identifies interferon-encompassing chromosome 9p21.3 deletions as mediators of immune evasion and metastasis
Authors: Francisco M. Barriga, Kaloyan M. Tsanov, Yu-Jui Ho, Noor Sohail, Amy Zhang, Timour Baslan, Alexandra N. Wuest, Isabella Del Priore, Brigita Meškauskaitė, Geulah Livshits, Direna Alonso-Curbelo, Janelle Simon, Almudena Chaves-Perez, Dafna Bar-Sagi, Christine A. Iacobuzio-Donahue, Faiyaz Notta, Ronan Chaligne, Roshan Sharma, Dana Pe’er, Scott W. Lowe
Journal: Nature Cancer (2022)

Abstract The most prominent homozygous deletions in cancer affect chromosome 9p21.3 and eliminate CDKN2A/B tumor suppressors, disabling a cell-intrinsic barrier to tumorigenesis. Half of 9p21.3 deletions, however, also encompass a type I interferon (IFN) gene cluster; the consequences of this co-deletion remain unexplored. To functionally dissect 9p21.3 and other large genomic deletions, we developed a flexible deletion engineering strategy, MACHETE (molecular alteration of chromosomes with engineered tandem elements). Applying MACHETE to a syngeneic mouse model of pancreatic cancer, we found that co-deletion of the IFN cluster promoted immune evasion, metastasis and immunotherapy resistance. Mechanistically, IFN co-deletion disrupted type I IFN signaling in the tumor microenvironment, leading to marked changes in infiltrating immune cells and escape from CD8 + T-cell surveillance, effects largely driven by the poorly understood interferon epsilon. These results reveal a chromosomal deletion that disables both cell-intrinsic and cell-extrinsic tumor suppression and provide a framework for interrogating large deletions in cancer and beyond.
ADRA1A–Gαq signalling potentiates adipocyte thermogenesis through CKB and TNAP
Authors: Janane F. Rahbani, Charlotte Scholtes, Damien M. Lagarde, Mohammed F. Hussain, Anna Roesler, Christien B. Dykstra, Jakub Bunk, Bozena Samborska, Shannon L. O’Brien, Emma Tripp, Alain Pacis, Anthony R. Angueira, Olivia S. Johansen, Jessica Cinkornpumin, Ishtiaque Hossain, Matthew D. Lynes, Yang Zhang, Andrew P. White, William A. Pastor, Maria Chondronikola, Labros Sidossis, Samuel Klein, Anastasia Kralli, Aaron M. Cypess, Steen B. Pedersen, Niels Jessen, Yu-Hua Tseng, Zachary Gerhart-Hines, Patrick Seale, Davide Calebiro, Vincent Giguère, Lawrence Kazak
Journal: Nature Metabolism (2022)

Abstract Noradrenaline (NA) regulates cold-stimulated adipocyte thermogenesis 1 . Aside from cAMP signalling downstream of β-adrenergic receptor activation, how NA promotes thermogenic output is still not fully understood. Here, we show that coordinated α 1 -adrenergic receptor (AR) and β 3 -AR signalling induces the expression of thermogenic genes of the futile creatine cycle 2,3 , and that early B cell factors, oestrogen-related receptors and PGC1α are required for this response in vivo. NA triggers physical and functional coupling between the α 1 -AR subtype (ADRA1A) and Gα q to promote adipocyte thermogenesis in a manner that is dependent on the effector proteins of the futile creatine cycle, creatine kinase B and tissue-non-specific alkaline phosphatase. Combined Gα q and Gα s signalling selectively in adipocytes promotes a continual rise in whole-body energy expenditure, and creatine kinase B is required for this effect. Thus, the ADRA1A–Gα q –futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis.
Prevalence of sleep disturbances in people with dementia living in the community: A systematic review and meta-analysis
Authors: Tala Koren, Emily Fisher, Lucy Webster, Gill Livingston, Penny Rapaport
Journal: Ageing Research Reviews (2022)

This study aimed to systematically review and meta-analyse the prevalence of sleep disturbances in people with dementia and examine demographic predictors and whether overall prevalence has changed over time. We searched Embase, MEDLINE and PsycINFO for studies reporting the prevalence of sleep disturbances in people with dementia living at home. We meta-analysed the data and calculated the pooled prevalence of sleep disturbances in people with dementia overall and in dementia subtypes. We used meta-regressions to investigate the effects of study characteristics, publication dates and participant demographics. Eleven studies fulfilled the inclusion criteria. The pooled prevalence of any symptoms of sleep disturbance was 26 % (95 % confidence intervals, CI: 23-30 %; n = 2719) and of clinically significant sleep disturbance 19 % (13-25 %; n = 2753). The pooled prevalence of sleep disturbance symptoms was significantly lower among people with Alzheimer's disease (24 %; 16-33 %, n = 310) than Lewy body dementia (49 %; 37-61 %, n = 65). Meta-regression analysis did not find that publication year, participant's age, sex and study quality predicted prevalence. Sleep disturbances are common among people with dementia living in the community, especially in Lewy body dementia. There was no change in prevalence according to publication dates, suggesting treatment has not improved over time.
Longitudinal transkingdom gut microbial approach towards decompensation in outpatients with cirrhosis
Authors: Jasmohan S Bajaj, Marcela Peña-Rodriguez, Alex La Reau, Wendy Phillips, Michael Fuchs, Brian C Davis, Richard K Sterling, Masoumeh Sikaroodi, Andrew Fagan, Amirhossein Shamsaddini, Zachariah Henseler, Tonya Ward, Puneet Puri, Hannah Lee, Patrick M Gillevet
Journal: Gut (2022)

Objective First decompensation development is a critical milestone that needs to be predicted. Transkingdom gut microbial interactions, including archaeal methanogens, may be important targets and predictors but a longitudinal approach is needed. Design Cirrhosis outpatients who provided stool twice were included. Group 1: compensated, group 2: 1 decompensation (decomp), group 3: &gt;1 decompensationwere followed and divided into those who remained stable or decompensated. Bacteria, viral and archaeal presence, α/β diversity and taxa changes over time adjusted for clinical variables were analysed. Correlation networks between kingdoms were analysed. Results 157 outpatients (72 group 1, 33 group 2 and 52 group 3) were followed and 28%–47% developed outcomes. Baseline between those who remained stable/developed outcome: While no α/β diversity differences were seen, commensals were lower and pathobionts were higher in those who decompensated. After decompensation: those experiencing their first decompensation showed greater decrease in α/β-diversity, bacterial change (↑ Lactobacillus spp, Streptococcus parasanguinis and ↓ beneficial Lachnospiraceae and Eubacterium hallii ) and viral change (↑Siphoviridae, ↓ Myoviridae) versus those with further decompensation. Archaea: 19% had Methanobacter brevii, which was similar between/within groups. Correlation networks: Baseline archaeal-viral-bacterial networks were denser and more homogeneous in those who decompensated versus the rest. Archaea-bacterial correlations collapsed post first decompensation. Lactobacillus phage Lc Nu and C2-like viruses were negatively linked with beneficial bacteria. Conclusion In this longitudinal study of cirrhosis outpatients, the greatest transkingdom gut microbial changes were seen in those reaching the first decompensation, compared with subsequent decompensating events. A transkingdom approach may refine prediction and provide therapeutic targets to prevent cirrhosis progression.
Designing receptor agonists with enhanced pharmacokinetics by grafting macrocyclic peptides into fragment crystallizable regions
Authors: Katsuya Sakai, Nozomi Sugano-Nakamura, Emiko Mihara, Nichole Marcela Rojas-Chaverra, Sayako Watanabe, Hiroki Sato, Ryu Imamura, Dominic Chih-Cheng Voon, Itsuki Sakai, Chihiro Yamasaki, Chise Tateno, Mikihiro Shibata, Hiroaki Suga, Junichi Takagi, Kunio Matsumoto
Journal: Nature Biomedical Engineering (2022)

Abstract Short half-lives in circulation and poor transport across the blood–brain barrier limit the utility of cytokines and growth factors acting as receptor agonists. Here we show that surrogate receptor agonists with longer half-lives in circulation and enhanced transport rates across the blood–brain barrier can be generated by genetically inserting macrocyclic peptide pharmacophores into the structural loops of the fragment crystallizable (Fc) region of a human immunoglobulin. We used such ‘lasso-grafting’ approach, which preserves the expression levels of the Fc region and its affinity for the neonatal Fc receptor, to generate Fc-based protein scaffolds with macrocyclic peptides binding to the receptor tyrosine protein kinase Met. The Met agonists dimerized Met, inducing biological responses that were similar to those induced by its natural ligand. Moreover, lasso-grafting of the Fc region of the mouse anti-transferrin-receptor antibody with Met-binding macrocyclic peptides enhanced the accumulation of the resulting Met agonists in brain parenchyma in mice. Lasso-grafting may allow for designer protein therapeutics with enhanced stability and pharmacokinetics.
Macrophage migration inhibitory factor promotes glucocorticoid resistance of neutrophilic inflammation in a murine model of severe asthma
Authors: Venkata Sita Rama Raju Allam, Stelios Pavlidis, Gang Liu, Nazanin Zounemat Kermani, Jennifer Simpson, Joyce To, Sheila Donnelly, Yi-Ke Guo, Philip M Hansbro, Simon Phipps, Eric F Morand, Ratko Djukanovic, Peter Sterk, Kian Fan Chung, Ian Adcock, James Harris, Maria B Sukkar
Journal: Thorax (2022)

Background Severe neutrophilic asthma is resistant to treatment with glucocorticoids. The immunomodulatory protein macrophage migration inhibitory factor (MIF) promotes neutrophil recruitment to the lung and antagonises responses to glucocorticoids. We hypothesised that MIF promotes glucocorticoid resistance of neutrophilic inflammation in severe asthma. Methods We examined whether sputum MIF protein correlated with clinical and molecular characteristics of severe neutrophilic asthma in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. We also investigated whether MIF regulates neutrophilic inflammation and glucocorticoid responsiveness in a murine model of severe asthma in vivo. Results MIF protein levels positively correlated with the number of exacerbations in the previous year, sputum neutrophils and oral corticosteroid use across all U-BIOPRED subjects. Further analysis of MIF protein expression according to U-BIOPRED-defined transcriptomic-associated clusters (TACs) revealed increased MIF protein and a corresponding decrease in annexin-A1 protein in TAC2, which is most closely associated with airway neutrophilia and NLRP3 inflammasome activation. In a murine model of severe asthma, treatment with the MIF antagonist ISO-1 significantly inhibited neutrophilic inflammation and increased glucocorticoid responsiveness. Coimmunoprecipitation studies using lung tissue lysates demonstrated that MIF directly interacts with and cleaves annexin-A1, potentially reducing its biological activity. Conclusion Our data suggest that MIF promotes glucocorticoid-resistance of neutrophilic inflammation by reducing the biological activity of annexin-A1, a potent glucocorticoid-regulated protein that inhibits neutrophil accumulation at sites of inflammation. This represents a previously unrecognised role for MIF in the regulation of inflammation and points to MIF as a potential therapeutic target for the management of severe neutrophilic asthma.
A gut-derived hormone suppresses sugar appetite and regulates food choice in Drosophila
Authors: Alina Malita, Olga Kubrak, Takashi Koyama, Nadja Ahrentløv, Michael J. Texada, Stanislav Nagy, Kenneth V. Halberg, Kim Rewitz
Journal: Nature Metabolism (2022)

Abstract Animals must adapt their dietary choices to meet their nutritional needs. How these needs are detected and translated into nutrient-specific appetites that drive food-choice behaviours is poorly understood. Here we show that enteroendocrine cells of the adult female Drosophila midgut sense nutrients and in response release neuropeptide F (NPF), which is an ortholog of mammalian neuropeptide Y-family gut-brain hormones. Gut-derived NPF acts on glucagon-like adipokinetic hormone (AKH) signalling to induce sugar satiety and increase consumption of protein-rich food, and on adipose tissue to promote storage of ingested nutrients. Suppression of NPF-mediated gut signalling leads to overconsumption of dietary sugar while simultaneously decreasing intake of protein-rich yeast. Furthermore, gut-derived NPF has a female-specific function in promoting consumption of protein-containing food in mated females. Together, our findings suggest that gut NPF-to-AKH signalling modulates specific appetites and regulates food choice to ensure homeostatic consumption of nutrients, providing insight into the hormonal mechanisms that underlie nutrient-specific hungers.
Gene editing strategies to treat lysosomal disorders: The example of mucopolysaccharidoses
Authors: Flávia Nathiely Silveira Fachel, Lariane Frâncio, Édina Poletto, Roselena Silvestri Schuh, Helder Ferreira Teixeira, Roberto Giugliani, Guilherme Baldo, Ursula Matte
Journal: Advanced Drug Delivery Reviews (2022)
A Pilot Randomized Controlled Trial of an Intervention to Improve Perception of Lung Function in Older Adults with Asthma
Authors: Jonathan M. Feldman, Jyoti Ankam, Michele Barry, Natalie Fruchter, Jacqueline Becker, Sunit Jariwala, Chang Shim, Juan P. Wisnivesky, Alex D. Federman
Journal: American Journal of Respiratory and Critical Care Medicine (2022)
Diverse Patterns and Clinical Significance of 11C-Methionine PET in Dysembryoplastic Neuroepithelial Tumors
Authors: Joo Whan Kim, Yeon-koo Kang, Jin Chul Paeng, Seung-Ki Kim, Byung Chan Lim, Ki Joong Kim, Ji Hoon Phi
Journal: Clinical Nuclear Medicine (2022)

Purpose Dysembryoplastic neuroepithelial tumors (DNETs) are slow-growing epilepsy-associated tumors. Low or normal 11 C-methionine (MET) PET uptake helps to differentiate DNETs from other low-grade gliomas. However, diverse MET-PET uptake in DNETs has been observed. The aim of this study is to measure the clinical significance and prognostic value of MET-PET in DNET management. Patients and Methods Retrospective review of 26 DNET patients was done. Clinical characteristics, radiologic findings, and visual and quantitative MET-PET results were analyzed. PET uptake was calculated as the tumor–to–homotopic mirror ratio (TNR m ) and tumor–to–contralateral cortex ratio (TNR c ). The clinical activity of the tumors at the time of PET was classified into active and quiescent groups. The surgical outcome was defined as a composite of 2 different aspects: tumor progression and/or clinical events such as seizure recurrence or tumor bleeding. Results Twenty-seven MET-PET examinations (20 initial MET-PET and 7 MET-PET during follow-up) were included. Clinically active tumors at the time of PET presented significantly higher values of TNR m and TNR c than quiescent tumors. High MET-PET uptake by visual grading, TNR m ≥ 1.90, and TNR c ≥ 1.85 exhibited poor prognosis for event-free survival. Conclusions MET-PET uptake correlates well with the clinical behavior of DNETs at the time of PET examination. Moreover, High MET-PET uptake is closely related to seizure recurrence if tumors are not entirely resected. Efforts to achieve gross total resection should be made for DNETs with high MET-PET uptake.
The Manifestation of a Patient With Myelofibrosis in 68Ga-DOTA-FAPI-04 PET/CT Mimicking “Super Bone Imaging”
Authors: Xue Li, Qian Zhao, Qianfeng Luo, Liming Chen, Zhanwen Huang
Journal: Clinical Nuclear Medicine (2022)

Abstract Primary myelofibrosis is a chronic inflammatory disease of the bone marrow. It progresses from an early robust inflammatory state to a more advanced fibrotic response, representing the advanced stage of the disease. We report a 50-year-old woman who was diagnosed with primary myelofibrosis. 18 F-FDG PET/CT showed mild uptake in diffuse sclerotic lesions in the bone matrix, whereas 68 Ga-DOTA-FAPI-04 showed intense uptake at the whole skeleton.
Brain PET Imaging of 11C-Methionine, 18F-FDG, and 18F-THK5351 in a Case of Lymphomatoid Granulomatosis
Authors: Mana Higashihara, Kenji Ishibashi, Aya M. Tokumaru, Kenji Ishii, Atsushi Iwata
Journal: Clinical Nuclear Medicine (2022)

A 52-year-old woman complained of upper respiratory symptoms and subsequently developed Wallenberg syndrome. Chest CT and brain MRI revealed multiple nodular lesions in the lungs and brain. She was pathologically diagnosed with low-grade lymphomatoid granulomatosis by lung biopsy. Brain PET examinations using 11C-methionine, 18F-FDG, and 18F-THK5351 were performed. Uptake of 11C-methionine and 18F-FDG was slightly increased in some lesions, likely reflecting the degree of inflammatory cell infiltration. 18F-THK5351 uptake was significantly increased in all lesions, likely reflecting the degree of reactive astrogliosis. This case illustrates the utility of PET studies for diagnosing lymphomatoid granulomatosis and provides insight into its pathophysiology.
68Ga-DOTA-FAPI-04 PET/CT Imaging in a Case of Radioactive Iodine–Induced Chronic Parotitis
Authors: Tingting Xu, Yan Zhang, Ruilin Wu, Haoyuan Ding, Yue Chen
Journal: Clinical Nuclear Medicine (2022)

68Ga-DOTA-FAPI-04 is a promising PET agent for tumor imaging. However, inflammatory lesions can also show increased FAPI uptake. Herein, we reported a 52-year-old woman who underwent total thyroidectomy for thyroid papillary carcinoma 1 year ago and underwent adjuvant radioiodine therapy 1 month later. After 131I therapy, she began to develop pain and swelling in bilateral cheeks, which developed into oral dryness. The patient was diagnosed with radioactive iodine-induced parotitis. 68Ga-DOTA-FAPI-04 PET/CT showed the density of bilateral parotid glands increased, and the volume decreased with intense tracer uptake. 99mTcO4- salivary gland scintigraphy showed decreased tracer uptake in the bilateral parotid glands.